Project Summary/Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease characterized by extensive desmoplasia caused
by the rapid expansion of cancer-associated fibroblasts (CAFs), resulting in the formation of dense stroma.
CAFs stimulate cancer progression by secreting a variety of factors that support cancer cells and facilitate
immunosuppression. In addition, they also secrete extracellular matrix (ECM) that provides survival and
invasion cues to cancer cells and impairs drug delivery. Recently, several populations of CAFs with distinct
functions have been characterized in PDA by our group and others using single cell RNA sequencing (scRNA
seq). One population is characterized as myofibroblastic CAFs (myCAFs), another population is characterized
as inflammatory CAFs (iCAFs), the third population was first identified as antigen-presenting CAFs (apCAFs),
which express MHC II molecules and can effectively present antigen to T cells. My preliminary data
demonstrated that apCAFs are mesothelial cells. Mesothelial cells form a continuous layer of epithelial cells
known as mesothelium. The mesothelium is traditionally thought to be a membrane providing a non-adhesive
surface covering organs and tissues. However, until the description of apCAF population, mesothelial cells
have been neglected as a potential functional constituent of the tumor microenvironment. My preliminary data
suggest that during PDA progression, mesothelial cells go through a mesothelial-fibroblastic transition (MFT),
in which they down-regulate MHC II molecules that are required for CD4+ T cells activation, and up-regulate
fibroblast genes that have been known to prevent T cell infiltration and activation. Peripheral T cell exclusion is
a major immune evasion phenotype in PDA, and my preliminary data show that this exclusion occurs at the
region where mesothelial cells are transitioning to CAFs. Therefore, MFT might be an important mechanism of
immune evasion and understanding this process is critical. In this proposal, I will test the hypothesis that the
fibroblastic transition of mesothelial cells promotes immune evasion in PDA and identify potential
strategies to inhibit this process. I propose the following two aims: Aim 1. Determine the fate of mesothelial
cells during PDA progression. Aim 2. Determine the functions of MFT on immune evasion. The outcome
of the proposed study has the potential to shift the paradigm of tumor microenvironment studies, identify novel
strategies to target CAFs and overcome resistance of immune therapies in PDA and other tumor types.